Diffuse intrinsic pontine glioma (DIPG)

Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive pediatric brain tumor that arises in a part of the brainstem, the pons.^1,2

DIPGs are the most common subtype of pediatric brainstem tumors, accounting for 80% of pediatric brainstem tumors.^1–3

Median age of diagnosis is around 6 or 7 years of age¹ – but prognosis is poor: median life expectancy is around 1 year, and 2-year survival is less than 10%.^1–3 This makes it a leading cause of brain tumor-related deaths among the pediatric population.² Such poor prognosis has been attributed to the tumor’s diffusive nature and its invasive spread.²

The underlying pathophysiology of DIPG is not clearly understood;⁴ however, the region- and age-specific nature of DIPGs suggests that a postnatal neurodevelopmental process is impaired.⁵ But this could be alongside dysregulation of the epigenome, which is thought to be a key factor in DIPG tumorigenesis.⁴

Potential DIPG biomarker

A precursor cell, Olig2 is present in the brainstem during infancy but not by age 2.⁵ Olig2 density increases again around 6 years of age, and coincides with the incidence of DIPG.⁵ Therefore, it may be possible that DIPGs originate from Olig2 and a neural precursor cell.⁵

Genetic mutations in DIPG

Tumor cell invasion is a complex process; however, recent gene sequencing studies have identified mutations that may contribute to the invasive spread of DIPG.²

DIPG is now thought to be characterized by oncohistone mutations in H3K27M, which occur in 80–85% of patients.^4,6 These mutations are thought to induce chromatin dysregulation and tumorigenesis.⁴ H3K27M mutations are associated with an aggressive tumor type and poor survival.⁴

ACVR1 mutations may occur in around 30% of DIPG cases.¹ A mutation in ACVR1 may facilitate early tumor progression along with other molecular abnormalities.¹

A mutation in TP53 occurs in 22–40% of DIPGs. When coupled with H3K27M mutations and usually PPM1D mutations, tumor cells are able to evade cell death and senescence through epigenetic dysregulation.¹ 

In the US, 200–300 new patients are affected every year.³ The reported incidence rate is 1–2:100,000 population.⁷

DIPGs represent 75–80% of brainstem tumors in children, making them the most common brainstem tumor type.^1,3 DIPG also represents 10–20% of all pediatric brain tumors.^1,8

The age of onset is in middle childhood, around 6–9 years of age.^1,7 However, a few outliers have been reported in patients at 1 and 26 years of age.⁵ There is an equal incidence distribution across males and females.⁵

Patients can present with symptoms that reflect the tumor’s location. For example, a tumor causing brainstem dysfunction or cerebrospinal fluid obstruction will have symptoms that show evidence of these malfunctions.^1,3 Because of the rapid progression of the disease, children may experience symptoms for <1 month before presenting at a clinic.^1,3

Abducens palsy, characterized by a dysconjugate gaze and diplopia, is typically the first symptom.⁹

Over 50% of patients are present with these classical triad of symptoms:^1,3,5,10

• Cranial nerve palsies, including facial asymmetry, facial weakness, and diplopia
• Long tract signs including hypertonia, hyperreflexia, clonus or motor deficits, and Babinski reflex
• Cerebellar signs including ataxia, dysmetria and dysarthria

Other symptoms can include behavioral changes, night terrors, difficulty at school, or even pathologic laughter.^3,5

Clinical history is typically used to diagnose DIPG, including time to presentation and physical symptoms, in addition to magnetic resonance imaging (MRI) results.^1,11 DIPG tumors are typically hypointense on MRI T1-weighted images, and hyperintense on T2-weighted/fluid-attenuated inversion recovery images.^1,5 Enhancement by gadolinium contrast media is either minimal or often absent – a key distinguishing feature of DIPG from pilocytic astrocytoma or other central nervous system tumors.^5,11  

The tumor may occupy over 50% of the pons axial diameter, including invasion of the basilar artery.¹ DIPG tumors rarely metastasize, showing preference for infiltrative and diffusive growth along nerve fiber tracts to thalamus and cerebellum regions.¹ 

Previously, classic findings from physical examination and imaging were sufficient for the diagnosis of DIPG, and confirmation using biopsy was deemed unnecessary due to tissue sampling in high-risk anatomic regions.^7,11 Advancements in diagnostic imaging techniques have further rendered biopsies unnecessary. This has resulted in a lack of DIPG samples for research. The perceived risk associated with obtaining a brainstem biopsy has exacerbated this issue.¹ However, the role of molecular diagnostics is growing to support improved diagnosis, support research, and for entry into clinical trials that require histological and molecular data.¹  

When tissue is available, diagnosis can be confirmed by histological review and can be supplemented by molecular testing.¹ Genetic sequencing techniques are used to confirm the presence or absence of mutations in H3.¹ Identifying the affected isoform can inform prognosis.¹

DIPGs can infiltrate beyond the pons, displaying highly diffuse and invasive growth. They commonly extend into other areas of the brain including the thalami, middle cerebellar peduncles, basal ganglia, or directly into the supratentorium.^2,5 After diagnosis, median survival is between 8 and 11 months⁵ and 2-year survival is less than 10%.^1–3 This makes it a leading cause of brain tumor-related deaths among the pediatric population.² 

Such poor prognosis has been attributed to the tumor’s location, diffusive nature and its invasive spread.^2,8

The invasion of tumor cells causes the pons to expand, distorting, displacing, and destroying nerve fiber tracts. The pons contains nuclei vital for life-sustaining functions, when this is damaged it can have significant effects, affecting prognosis.⁸ For example, invasion of tumor cells to the adjacent cerebellum are associated with impairment of gait, coordination, and speech.^8,12 To improve quality of life, survival rates, and reduce secondary neurological effects, combating invasion is regarded as a potential pathway.² Together, these findings indicate the role of invasion in worsening prognosis, although local progression is viewed as the main problem in DIPG.²  

1. Srikanthan D, Taccone MS, Van Ommeren R, et al. Chin Neurosurg J 2021;7:6.
2. Kluiver TA, Alieva M, van Vuurden DG, et al. Front Oncol 2020;10:92.
3. Warren KE. Front Oncol 2012;2:1–9.
4. Balakrishnan I, Danis E, Pierce A, et al. Cell Rep 2020;33(3):108286.
5. Vitanza NA, PG Fisher, Deisseroth MMD. 128 – Diffuse Intrinsic Pontine Glioma. In: Swaiman KF, Ashwal S, Ferriero DM, Schor NF, Finkel RS, Gropman AL, Pearl PL, Shevell MI, eds. Swaiman’s Pediatric Neurology (Sixth Edition). Edinburgh:Elsevier 2017;991–994.
6. Buczkowicz P, Hoeman C, Rakopoulos P, et al. Nat Genet 2014;46:451–456.
7. Pellot JE, De Jesus O. Diffuse Intrinsic Pontine Glioma. [Updated 2023 Aug 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK560640/.
8. Valvi S, Gottardo NG. Diffuse intrinsic pontine glioma. In: Agrawal A, Moscote-Salazar LR, editors. Brain Tumors – An Update. London: IntechOpen;2018:35–70.
9. Vitanza NA, Monje M. Curr Treat Options Neurol 2019;21:37.
10. Vanan MI, Eisenstat DD. Front Oncol 2015;5:237.
11. Schroeder K, Hoeman C, Becher O. Pediatr Res 2014;75:205–209.
12. Johung TB, Monje M. Curr Neuropharmacol 2017;15:88–97.